Greene Square was laid out in 1799 at Houston and President Streets and named for General Nathanael Greene. Greene commanded the Southern army in the Revolution and afterward settled at Mulberry Grove, the estate above Savannah where he died in 1786. He is actually buried in Johnson Square. The oldest buildings on the square are believed to date from the same year as the square itself.

For much of the 19th century, Greene Square was the center of Savannah's African American community. The Second African Baptist Church, founded in 1802 and rebuilt after a fire in 1925, stands on its northwest trust lot. There, in January 1865, General Sherman announced Special Field Orders No. 15, the 'forty acres and a mule' order. Nearby, at 513 East York Street, lived Catherine DeVeaux, whose family included Jane DeVeaux, who ran a secret school to teach Black children to read when that was illegal. The house at 117–119 Houston Street, built in 1810, served as a girls' orphanage until 1838. Today the square is a quiet public green, open at all hours, surrounded by private homes.